In Search of Safe and Effective Oral Anticoagulation

There is a large gap between the need for anticoagulation and the use of drug therapy for this purpose in ambulatory care. Major lower-extremity orthopedic surgery such as total hip replacement and total knee replacement are associated with an increased risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to symptomatic outcomes such as pulmonary embolism (PE). Prophylaxis and treatment of patients with symptomatic VTE occurs in 2 phases. Initial therapy focuses on rapid achievement of effective anticoagulation and usually involves subcutaneous low-molecular-weight heparin. Long-term prophylaxis with the vitamin K antagonist, warfarin, reduces the risk of recurrent VTE from about 27% (without prophylaxis or inadequate prophylaxis) to 4% during the first 3 months of observation.


E D I T O R I A L S U B J E C T S -I N T H I S I S S U E A N D I N P R E V I O U S I S S U E S ss In Search of Safe and Effective Oral Anticoagulation
There is a large gap between the need for anticoagulation and the use of drug therapy for this purpose in ambulatory care. 1,2 Major lower-extremity orthopedic surgery such as total hip replacement and total knee replacement are associated with an increased risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to symptomatic outcomes such as pulmonary embolism (PE). 3 Prophylaxis and treatment of patients with symptomatic VTE occurs in 2 phases. Initial therapy focuses on rapid achievement of effective anticoagulation and usually involves subcutaneous low-molecular-weight heparin. Long-term prophylaxis with the vitamin K antagonist, warfarin, reduces the risk of recurrent VTE from about 27% (without prophylaxis or inadequate prophylaxis) to 4% during the first 3 months of observation. 4 While warfarin is a marvelous, life-saving drug, the safety risk from bleeding, need for continuous monitoring, and interaction with many common drugs limit its more widespread and long-term use. The search for a suitable alternative that would provide similar efficacy in anticoagulation with lower risk of bleeding has centered on ximelagatran (Exanta) in recent years, an oral direct thrombin inhibitor (DTI). However, large expectations for an alternative to warfarin therapy with ximelagatran were dashed on September 10, 2004, when a U.S. Food and Drug Administration (FDA) advisory panel declined to recommend approval of ximelagatran because of safety concerns. 5 After 3 months of therapy with ximelagatran, 546 (7.9%) patients had an alanine aminotransferase (ALT) value more than 3 times the upper limit of normal versus 1.2% for comparators. 6 The panel also expressed concern over the apparent 3-fold increased risk of heart attacks in short-term use in knee-surgery patients. At the time of the FDA advisory panel decision more than a year ago, ximelagatran was approved for use in Europe for short-term therapy (12 days) in knee surgery patients.
Atrial fibrillation (AF) is the most common dysrrhythmia seen by clinicians, and it commonly requires anticoagulation therapy for primary prevention of strokes or other embolic events. Decision analysis in the treatment guidelines for AF from the Agency for Healthcare Research and Quality (AHRQ) indicated that aspirin is the most cost-effective therapy for patients at low risk of stroke (approximately 1% per year), and warfarin was determined to be the most cost effective when the risk of stroke was judged to be high (10% or higher per year). 7 For patients at intermediate risk (3% to 6% per year) of ischemic stroke, the choice between aspirin and warfarin is less clear and depends on the assumption regarding quality of life on warfarin versus aspirin therapy. Overall, for every 1,000 patients with AF who are treated with warfarin for 1 year, 30 strokes are prevented at the expense of 6 major bleeds. 4 In a cohort study of 11,526 adult members of the Kaiser The benefit of warfarin is realized at an increase in risk, but lower-intensity warfarin therapy appears to reduce efficacy without reducing the risk of bleeding. A randomized controlled trial (RCT) of 738 patients who had completed 3 or more months of warfarin therapy for unprovoked VTE found, after 2.4 years of follow-up, that those randomized to a target international normalized ratio (INR) of 2.0 to 3.0 (the conventional intensity level) experienced 0.7 recurrent VTEs per 100 personyears compared with 1.9 recurrent VTEs per 100 person-years for patients assigned to lower-intensity warfarin (target INR of 1.5 to 1.90). The HR was 2.8 (95% CI, 1.1-7.0). 9 A major bleeding episode occurred in 9 low-intensity patients (1.1 events per 100 person-years) versus 8 in the conventional group (0.9 events per 100 person-years); HR, 1.2. There was no significant difference in the frequency of overall bleeding between the 2 groups (HR, 1.3).
The length of anticoagulant therapy is nearly as important as the intensity of anticoagulation in the prevention of recurrent VTE. In a meta-analysis of RCTs with results published from 1969 through 2004 in PubMed, EMBase Pharmacology, the Cochrane database, clinical trial Web sites, and a hand search of reference lists, Ost et al. determined that the incidence of recurrent VTE with long-term (>6 months) anticoagulation therapy in patients with a first episode of VTE (or therapy that involved anticoagulation with one or more agents) was 0.020 events per person-year (i.e., 1 in 50) compared with a rate 6 times higher (0.126 events per person-year) for shorter therapy (P <0.001). 10 The authors concluded that the optimum length of warfarin therapy was not clear, but 6 or more months of treatment appeared to be beneficial, particularly for patients at higher risk, even though the duration of anticoagulation beyond 6 months results in a relatively modest incremental risk reduction. What is more, this study pointed out that (a) the number needed to treat to prevent 1 VTE event with long-term anticoagulation would be approximately 50 (95% CI, 25-1,000), (b) the effect size with lifelong therapy is much larger since the number needed to treat to prevent 1 VTE event with lifelong anticoagulation would be approximately 9 (95% CI, 7-14), but (c) the relative amount of harm that is associated with each adverse outcome is important to consider since, for example, the damage from an intracranial hemorrhage can be much more serious than a VTE of the lower extremity. During therapy with vitamin K antagonists, the risk of recurrence is very effectively reduced-by approximately 90%-to 0.7 episodes per 100 person-years. In the 6 to 12 months immediately after the discontinuation of therapy, a catch-up phenomenon occurs, resulting in an absolute incidence of recurrence of VTE of 5% to 10%. This phenomenon has been observed after 3, 6, and 12 months of vitamin K antagonist therapy and, therefore, suggests that prolonging this therapy delays recurrence until the therapy is stopped, rather than reducing the risk of recurrence except in patients at high risk of recurrent VTE. 11 During the subsequent years, the risk of recurrence stabilizes, and the annual incidence of recurrence is 1% to 2%. 12 The American Heart Association estimates that about 15% of all strokes in the United States occur in people with AF, 13 and analysis of medical therapy of AF, using data from the National Ambulatory Medical Care Survey (NAMCS), showed that fewer than half of AF patients at risk for stroke received anticoagulation therapy in the United States from 1991 through 2000. 14 While the NAMCS data were encouraging in the increased incidence of oral anticoagulant use, from 28% in 1991-1992 to 41% in 1999-2000 (P =0.01 for trend), and the greatest increase in patients aged 80 years and older (14% to 48%, P <0.001 for trend), only 46.5% of patients at high risk for stroke were taking anticoagulants in 1999-2000.
A retrospective analysis of the medical records of 3,778 patients from 38 U.S. hospitals for dates of service between July 1, 2000, and June 30, 2003, found that even when hospitalized, patients at high risk of stroke may not receive anticoagulation therapy: (a) only 54.7% of patients with AF at high risk of stroke received warfarin and 20.6% received neither aspirin nor warfarin; (b) only 75.5% of patients with acute myocardial infarction received aspirin on arrival at the hospital and only 85.6% received prophylaxis with either a parenteral anticoagulant or oral warfarin; (c) in 49.4% of patients with DVT, PE, or both who received unfractionated or low-molecular-weight heparin, the anticoagulation therapy was discontinued before an INR of 2.0 or greater was achieved for 2 consecutive days; and (d) patients with DVT or PE were rarely discharged from the hospital with bridge therapy (an injectable anticoagulant agent plus warfarin), although the length of hospitalization was significantly shorter for injectable anticoagulant plus warfarin compared with discharge with warfarin alone (4.0 vs. 8.1 days, P <0.001). 15 Maximization of the market opportunity for a warfarin replacement will, at some point, involve consideration of the economic consequences and opportunities associated with recurrent VTE events. In this issue of JMCP, the manufacturer of ximelagatran sponsored research reported by Bullano et al. regarding direct hospital and medical costs associated with recurrent VTEs, obtained from examination of administrative claims data from a managed care organization (MCO) composed of approximately 11 million members. 16 A cohort of 2,147 patients was identified by an incident in-hospital VTE event consisting of DVT, PE, or both DVT + PE, indicating a prevalence of 2.04 VTE patients per 100,000 MCO members. The average cost per recurrent VTE event that required rehospitalization was $14,975. During the postindex period, a total of 612 of the 2,147 patients experienced an average of 2.43 bleed events that did not require hospitalization, at a mean cost of $239 per event.
A few other points are notable in the study by Bullano et al. VTE was not necessarily the principal index diagnosis; i.e., these VTE patients could have been admitted for any principal diagnosis at the index hospitalization. The claims were for sick patients, including 59.2% with a history of or active malignancy, 24.5% with a coincident diagnosis of trauma, and 22.9% with a coincident diagnosis of AF. Of the 26,103 VTE patients identified initially, 13,703 (57% of the 23,956 excluded patients) were excluded for not having at least 1 pharmacy claim for an anticoagulant after hospital discharge. Warfarin treatment following the incident VTE event was administered to 97.3% of patients, for an average of 6.7 (median 5.0) months, but the standard deviation was 6 months, and warfarin therapy was defined by as little as 1 pharmacy claim. The cost of warfarin drug therapy was low, just $19.40 per patient per month. In the nearly 2 years of average follow-up, 534 (24.9%) experienced an average of 1.24 bleed or recurrent VTE events that required hospitalization. Stated another way, the average cost of hospitalization for recurrent VTE or bleed events was $3,729 over nearly 2 years of follow-up (or $2,101 per patient per year) for these patients with an index VTE event during a prior hospitalization for any reason.
Among the several limitations of the study by Bullano et al. was the absence of data regarding the availability and use of anticoagulation management services for these MCO members. We do not know how many of the 534 patients with a recurrent VTE event did not receive care from an anticoagulation management service. We also do not know the INR laboratory values for any of these patients during follow-up or when the recurrent VTE event occurred relative to discontinuation of warfarin (or other antithrombotic) therapy. Left to other researchers is investigation of the relationship of recurrent VTE cost to the length and intensity of warfarin anticoagulant therapy and the magnitude of the effect of an anticoagulation management service on clinical and cost outcomes in these patients.
The  10. 17 More warfarin patients (86%) completed the study than did ximelagatran patients (82%), and the total mortality was approximately the same in both groups (4.6%). The rate of secondary events in each group was similar, with the exception of bleeding complications, which occurred in 25.8% of patients per year in the ximelagatran group versus 29.8% in the warfarin group; relative risk reduction 14% (95% CI, 4-22); P = 0.007. However, the ximelagatran patients were far more likely (6.1% vs. 0.8% for warfarin) to experience ALT levels at least 3 times the upper limit of normal within the first 6 months of the trial. 18 In the ESTEEM (Efficiency and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage) trial, elevation of ALT serum levels to more than 3 times the upper limit of normal occurred in 11% of ximelagatran patients treated for 6 months versus 2% for placebo. 19 In SPORTIF V, 3,922 AF patients with at least 1 stroke risk factor at 409 North American sites were randomized to receive adjusted-dose warfarin (target INR 2.0 to 3.0) or fixed-dose oral ximelagatran (36 mg twice daily). 20 The primary event rates (ischemic and hemorrhagic strokes and systemic embolic events) over an average 20 months of follow-up were 1.2% per year in the warfarin group and 1.6% per year in the ximelagatran group, an absolute difference of 0.45% per year (95% CI, -0.13 to 1.03; P <0.001). When all-cause mortality was included with the primary events, the rate difference between groups by intent to treat was 0.10% per year (95% CI, -0.97 to 1.18; P = 0.86). Rates of disabling or fatal stroke, hemorrhagic stroke, and major bleeding did not differ significantly between groups, but serum ALT levels rose transiently above 3 times the upper limit of normal in 6.0% of patients on ximelagatran versus 0.8% of patients on warfarin (P < 0.001) within the first 6 months of treatment.
In 2003, the year before the FDA decision to not approve ximelagatran for use in the United States, the medical literature was already peppered with observers almost giddy over the expectant demise of anticoagulation clinics engaged in warfarin monitoring and management. 21,22 Just a few months later, in early 2004, there was increased recognition that, while the occurrence of major bleeding seems lower with ximelagatran, it is necessary to treat 167 patients with ximelagatran to prevent 1 major bleeding event per year compared with warfarin, but the number needed to harm (for increased concentration of liver enzymes) is 19 patients on ximelagatran. 23 The clinical trials of ximelagatran, all sponsored by the manufacturer, have generally found (a) comparable efficacy to enoxaparin and warfarin but (b) elevated liver enzymes and a possible increased risk of myocardial ischemia. In a randomized double-blind trial with concealed allocation (level of evidence=1b) 24 of 2,489 patients with acute DVT, including one third with PE, Fiessinger et al. found 36 mg of ximelagatran twice daily for 6 months was comparable to enoxaparin 1 mg per kg twice daily for 5 to 20 days followed by warfarin adjusted to an INR range of 2.0 to 3.0. 25 The THRIVE (Thrombin Inhibitor in Venous Thromboembolism) Treatment Study reported by Fiessinger et al. found an incidence of 2.1% recurrent DVT in the ximelagatran patients versus 2.0% in the enoxaparin/warfarin patients (an insignificant absolute difference of 0.2%), but the ximelagatran patients were more likely to have increased levels of ALT more than 3 times the upper limit of normal (9.6% vs. 2.0%). Symptomatic myocardial ischemia leading to hospitalization was noted in 10 patients (0.8%) treated with ximelagatran versus 1 patient treated with enoxaparin/warfarin (0.08%) (P = 0.006).
EXULTA (Exanta Used to Lessen Thrombosis A) was a randomized, double-blind trial involving 1,851 patients undergoing total knee replacement. EXULTA compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. 26 For the primary outcome measures (composite end point of venous thromboembolism and death from all causes), ximelagatran appeared superior to warfarin, (20.3% vs. 27.6%; P = 0.003), and major bleeding was not different, 0.8% for ximelagatran versus 0.7% for warfarin. For the composite secondary end point, proximal DVT, PE, or death, the difference was also not significant (2.7% for ximelagatran vs. 4.1% for warfarin; P = 0.17). Criticism followed publication of the EXULTA trial, including the point that the apparent small superiority of ximelagatran over warfarin could have been predicted from the study design and the slower onset of action of warfarin since the therapeutic INR range had not been reached in 35% of the patients in the warfarin group by postoperative day 3 and in 24% of the patients in this group by the day of venography. 27 Experts have leveled additional criticism at the study designs in clinical trails that have alleged value of ximelagatran. For example, Schulman et al., in a double-blind, multicenter trial (THRIVE III) of 1,233 patients with VTE, found ximelagatran superior to placebo in preventing recurrent VTEs over an 18-month follow-up period. 28 All patients had received 6 months of anticoagulant therapy followed by an average of 18 months of secondary prevention with either ximelagatran 24 mg twice daily or placebo. The occurrence of the primary end point, symptomatic recurrent VTE, was confirmed in 12 of 612 patients assigned to ximelagatran (2.0%) versus 71 of 611 patients (11.6%) assigned to placebo (HR, 0.16; 95% CI, 0.09-0.30; P <0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients in the ximelagatran group versus 111 patients in the placebo group (HR, 1.19; 95% CI, 0.93-1.53; P = 0.17). The incidence of major hemorrhage was low (6 events in the ximelagatran group and 5 in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the ALT level to more than 3 times the upper limit of normal was 6.4% in the ximelagatran group compared with 1.2% in the placebo group (P <0.001). Boger et al. criticized the Schulman study for inclusion of a large number (129) of high-risk patients in the placebo group, 29 citing the increased risk of recurrent VTE after an episode of VTE in patients with cancer or known recurrent VTE, which can be reduced by prolonged anticoagulation. Vaknansky et al. complained about the 97 patients (16%) in the placebo group who had a history of recurrent VTE of up to 4 events each. 30 There have been at least 10 large controlled, clinical trials of DTIs in prophylaxis of treatment of VTE, including 5 for postoperative initiation of prophylaxis of VTE, 3 for preoperative initiation of prophylaxis of VTE, and 1 each for initial treatment of acute VTE and long-term secondary prophylaxis of VTE. 31 Nevertheless, (a) there are few indications for DTIs and (b) the DTIs have demonstrated comparable but not superior efficacy, with similar safety, to heparin, enoxaparin, or warfarin. While 4 parenteral DTIs have been approved by the FDA, ximelagatran is the only oral DTI that has shown promise in AF. Unfortunately, ximelagatran is tripped up by concern regarding hepatoxicity. Therefore, the search continues for safe and effective oral anticoagulation, and the pharmacist specialists and other clinicians involved in warfarin management services do not appear to be in immediate danger of unemployment.